1. Field of the Invention
The present invention relates to the use of certain nitrogen containing heterocyclics for systemic control of ectoparasites on homoiothermic or warm blooded animals and in another embodiment, the use of combinations of the nitrogen containing heterocyclics with other systemically active ingredients to control both ectoparasites and endoparasites.
2. Background of the Invention
Bloodsucking ectoparasites of the order Insecta include such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), as well as lice, mosquitos, tabanids, tsetse and other biting flies, and Acarina such as Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros (ticks), and the like, infest or attack many useful homoiothermic animals including farm animals such as cattle, swine, sheep, goat, poultry such as chicken, turkeys and geese, fur bearing animals such as mink, foxes, chinchilla, rabbits and the like, and pet animals such as dogs and cats.
Ticks are described as hard ticks or soft ticks and are characterized as one host, two host, or three host ticks. They attach to a suitable host animal and feed on blood and body fluids. Engorged females detach and drop from the host and lay large numbers of eggs (2,000 to 20,000) in a suitable niche in the ground or in some other sheltered location in which hatching occurs. The larva then seek a host from which to obtain a blood meal. Larvae of one host ticks molt on the host twice to become nymphs and adults without leaving the host. Larvae of two and three host ticks drop off the host, molt in the environment and rind a second or third host (as nymph or adult) on which to feed.
Ticks are responsible for the transmission and propagation of many human and animal diseases throughout the world. Ticks of major economic importance include Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma, and Dermacentor. They are vectors of bacterial, viral, rickettsial and protozoal diseases, and cause tick paralysis and tick toxicosis. Even a single tick can cause paralysis consequent to injecting its saliva into its host in the feeding process. Tick-borne diseases are usually transmitted by multiple-host ticks. Such diseases, including Babesiosis, Anaplasmosis, Theileriosis and Heart Water are responsible for the death and/or debilitation of vast numbers of pet and food animals throughout the world. In many temperate countries, Ixodid ticks transmit the agent of a chronic, debilitating disease, Lyme disease, from wildlife to man. In addition to disease transmission, ticks are responsible for great economic losses in livestock production. Losses are attributable not only to death, but also to damage of hides, loss of growth, reduction in milk production, and reduced grade of meat. Although the debilitating effects of tick infestations on animals have been recognized for years and tremendous advances have been made in tick control programs, no entirely satisfactory methods for controlling or eradicating these parasites have been forthcoming, and ticks have often developed resistance to chemical toxicants and dependent control measures.
Infestation of pets by fleas has long been a nuisance to pet owners. Because fleas are able to survive and multiply under a wide range of environmental conditions, controlling flea infestation requires a multifaceted program that must be vigorously applied to achieve any measure of success. Adult fleas live in the coat of the cat or dog and feed on blood. Male and female fleas mate still in the animal's coat and the female flea lays her eggs. The eggs do not adhere to the fur, but fall off and are distributed to the animal's environment. By this mechanism, while the total environment of the pet animal is infested with flea eggs, infestation is greatest in locations where the pet spends most of its time. Eggs hatch to larvae in about two days. There are three larval stages, each lasting about three days. In the last stage, the larva spins a cocoon and transforms into a pupa. Under optimum conditions (i.e., 33.degree. C. and 65% relative humidity), eggs develop through larvae to pupae in about 8-10 days. After a further period of approximately 8 days, the pupae develop into young adult fleas in the cocoon, still dispersed in the pet's environment. These pre-emerged adult fleas wait in their pupae until they sense, by carbon dioxide tension and/or vibrations, the presence of an animal host, and then emerge explosively and jump into the air and onto the passing host. Under suitable environmental conditions of temperature and humidity, unfed emerged fleas that fail to find a host can survive for some time in the environment, waiting for a suitable host. It takes at least three weeks for eggs to develop to pre-emerged adults, able to reinfest a host animal. However, the pre-emerged adults can remain viable in the cocoon for months, as long as one year. In addition, under sub-optimal temperature conditions, it can take 4-5 months for eggs to develop into pupae containing pre-emerged adults. Fleas require a blood meal in order to become sexually mature and able to reproduce. After their first blood meal, they undergo a shift in metabolism such that they cannot survive for any time off the host. The blood must come from the correct animal and the female flea's appetite requires that it consumes as much as 5 times its body weight of blood each day. The long life cycle, and especially, the extended period of pre-emergence dormancy, has made flea control with compounds applied topically to pet animals difficult and not entirely satisfactory. Most topically applied active ingredients have a limited residual effect, thus reinfestation by newly-emerged adults from the pet's environment is a constant problem.
Infestation of dogs and cats with fleas has several undesirable effects for the animals and their owners. Such undesirable effects include local irritation and annoying itching, leading to scratching. A high proportion of pet animals, particularly dogs, become allergic to flea saliva, resulting in the chronic condition known as flea bite allergy (or flea allergy). This condition causes the animal to bite and scratch, leading to excoriation of the skin, secondary pyogenic infection, hair loss, and chronic severe inflammatory skin changes. Furthermore, most dogs and cats that are infested with fleas also become infected with Dipylidium caninum, the tapeworm transmitted by fleas.
In prolonged absence of a suitable animal, newly emerged fleas attack any mammal, including humans, although they are not capable of full reproductive potential if human blood is their sole source of nutrition. Even in the presence of the pet animal, the owner may be bitten by fleas. Some humans may suffer allergic skin diseases as a result of being bitten by dog and cat fleas.
Since, like most insects, fleas can adapt to survive exposure to normally toxic agents, and the tolerance of dogs and cats to chemical agents varies, it is desirable to have a multiplicity of agents and methods available for controlling fleas. Prior art methods have included numerous toxic agents such as organophosphates (e.g., chlorpyrifos), carbamates (e.g., Carbaryl), pyrethroids (e.g., natural pyrethrins and permethrin), and other topical insecticides formulated and designed to kill the adult flea after their application to the pet. Many of the effective residual action toxic agents against fleas, such as DDT, benzene hexachloride, and other chlorinated hydrocarbon insecticides, have been banned from most countries because of environmental persistence of residues and their effect on certain wildlife. Others have been banned because of long-term health risks, including risks of cancer to chronically exposed humans. In the United States, even currently approved and available toxic agents that are effective against fleas, some only briefly, are under scrutiny because of concerns for long-term health hazards to pets and to their owners. These considerations have limited utility of insecticidal and acaricidal toxic compounds for control of fleas and ticks on pet animals and of ectoparasites on animals in general.
In addition to numerous insecticidal compositions aimed at controlling ectoparasites, systemic agents directed against ectoparasites have been suggested. For example, U.S. Pat. Nos. 3,962,458 and 4,031,239 disclose the application of various cyclopropane carboxylate compounds (pyrethroids) for controlling ectopamsites by systemic treatment of warm blooded animals. U.S. Pat. No. 4,006,236 discloses the systemic use of substituted octahydrophenanthridines. U.S. Pat. No. 4,053,631 discloses the systemic control of ectoparasites with alpha-cyano-m-phenoxybenzyl alpha-c1-c4alkyl-2-naphthaleneacetates. U.S. Pat. No. 4,323,582 discloses the systemic use of lower alkanolamines to repel bloodsucking parasites.
U.S. Pat. Nos. 4,089,975 and 4,092,421 disclose the feed-through administration of certain nitrogen containing heterocyclics for the control of manure-breeding insects by orally administering an insecticidally effective amount of the compound to a warm blooded animal. These applications indicate a feed-through mechanism wherein the active compound is orally administered to the host animal, passes unmetabolized through its digestive system, and is excreted in an insecticidally active form. This mechanism implies poor absorption of these compounds and does not suggest that nitrogen containing heterocyclic compounds would pass into the bloodstream of the animal and circulate in an active form therein.
Using as systemic agents the classes of methoprene-like juvenile hormones, flea growth inhibiting benzoylurea derivatives, and flea growth inhibiting triazine derivatives is disclosed in U.S. Pat. No. 4,973,589. Ovicidal activity is demonstrated by certain triazine derivatives, as well as for benzoylurea derivatives in U.S. Pat. No. 4,973,589 but no examples are given for the juvenile hormone class. Ovicidal activity in a target species has been reported for the juvenile hormone type materials, but only when applied topically to the animal.
Due to the variability of toxic effects in various animal species, and the high dose rates required for systemic effects with many of the prior art compounds, it is desirable that additional alternative control agents be made available. Certain substituted heterocyclics of known insecticidal activity are disclosed in U.S. Pat. Nos. 4,970,222, 4,879,292 and 4,751,223. However, these juvenile hormone-like nitrogen containing heterocyclic compounds have not heretofore been suggested as systemically administered ovicidal agents wherein an ovicidally effective dose is administered to the target ectoparasite when it feeds on the blood of the treated animal.
In many areas of the world, the environmental conditions and methods of maintaining animal populations that favor multiplication and survival of ectoparasites, similarly encourage the proliferation and spread of endoparasites, both those with a free living life cycle (e.g., intestinal roundworm parasites of the order Nematoda) and those that depend on transmission by vectors (e.g., lung, lymphatic and blood vascular dwelling parasites of the same order). Examples of intestinal parasites that flourish in these favorable conditions are ascarids and hookworms of dogs and cats. Intestinal parasites of the same order are also a major problem for the food and recreational animal industry, parasiting cattle, sheep, swine and horses. An example of a vector transmitted internal parasitic nematode is heartworm of dogs and, to a lesser extent cats, transmitted by mosquitoes. Because of the requirements for similar environmental conditions and methods of animal management, it is extremely common for companion and economic animals to be at the same time exposed to and infected by endoparasites and infested by ectoparasites such as fleas, ticks, lice, mange mites, and biting ties, including the mosquito, which is the vector for a most important endoparasite, heartworm. There is consequently an overwhelming need for a convenient single method of treatment that would prevent and treat both endoparasite infections and ectoparasite infestations.